Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/429—Thiazoles condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/08—Bronchodilators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/04—Antipruritics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/10—Anti-acne agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/16—Otologicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
  • C07D277/84—Naphthothiazoles

Definitions

• Phosphatidylinositol-3-kinases are a subfamily of the lipid kinases which catalyse the transfer of a phosphate group to the 3′-position of the inositol ring of phosphoinositides (Vanhaesebroeck and Waterfield, Exp Cell Res. 1999 Nov. 25; 253(1):239-54).
• PI3-kinases may be divided into various classes.
• the members of the receptor-regulated class I are heterodimeric enzymes which are made up of a catalytic subunit (p110) weighing 110-120 kDa and a non-catalytic subunit (p50, p55, p85, p101) weighing 50-101 kDa.
• the most highly conserved region in all the PI3-kinases is the C-terminally situated kinase domain. It has structural features which can also be found in the majority of known protein kinases. These also include e.g. highly conserved amino acids which are responsible for the coordination of the ATP molecule (Walker et al., Nature. 1999 Nov. 18; 402(6759):313-20).
• PI3-kinases Three of the four members of the class I PI3-kinases associate constitutively with an adaptor subunit weighing 50-85 kDa, of which p85 is the prototype. The interaction takes place via the so-called p85 binding domain which can be found on the catalytic subunits of the PI3-kinase ⁇ , ⁇ and ⁇ . The three forms are grouped in class IA on account of this structural feature.
• the catalytic subunit ⁇ of the PI3-kinase, p110 ⁇ associates instead with a regulatory protein weighing 101 kDa, which is known as p101. It constitutes Class IB of the PI3-kinases—of which it is currently the sole member.
• the PI3-kinase ⁇ , ⁇ and ⁇ are activated predominantly by receptor-tyrosine-kinases (RTKs) or soluble tyrosine kinases.
• RTKs receptor-tyrosine-kinases
• soluble tyrosine kinases The p85-subunit serves as an adaptor, as it is able to recognise and bind the phosphorylated tyrosine groups of specific amino acid sequences (YxxM) with its SH2 domains.
• the PI3K ⁇ on the other hand is activated mainly by G ⁇ -subunits which are released from heterotrimeric G-proteins after activation of heptahelical receptors.
• PI3-kinases are involved in uncontrolled cell growth and differentiation processes.
• the first detected PI3-kinase activity was associated with the transforming activity of viral oncogenes, such as e.g. the middle T antigen of polyomaviruses, Src tyrosine kinases or activated growth factors (Workman, Biochem Soc Trans. 2004 April; 32(Pt 2):393-6).
• viral oncogenes such as e.g. the middle T antigen of polyomaviruses, Src tyrosine kinases or activated growth factors (Workman, Biochem Soc Trans. 2004 April; 32(Pt 2):393-6).
• tumours such as e.g. breast cancer, ovarian or pancreatic carcinoma
• Akt/PKB an overactivity of Akt/PKB, which is activated directly by the lipid products of class I PI3-kinases and thus transmits the signals on into the cell.
• PIK3CA-gene which codes for p110 ⁇ has a high mutation frequency in various types of tumour, such as colon, breast or lung carcinomas, some examples of which were able to be characterised as activating mutations (Samuels et al., Science. 2004 Apr. 23; 304(5670):554).
• PI3K ⁇ The most recent member of the class IA PI3-kinases, PI3K ⁇ , is expressed more restrictively than PI3K ⁇ and ⁇ .
• PI3K ⁇ The most recent member of the class IA PI3-kinases, PI3K ⁇ , is expressed more restrictively than PI3K ⁇ and ⁇ .
• knock-in mice in which the catalytic subunit of PI3K ⁇ , p110 ⁇ , had been replaced by an inactive mutant, it was demonstrated that this PI3K-isoenzyme plays a specific part in the signal transmission of B- and T-lymphocytes after antigen receptor stimulation (Okkenhaug et al., Science. 2002 August; 297(5583):1031-4). These are mechanisms which play a part especially in autoimmune diseases such as e.g. Crohn's disease or rheumatoid arthritis.
• the PI3K ⁇ is activated almost exclusively by G i -coupling heptahelical receptors.
• neutrophils in mice which express no PI3K ⁇ no PI3,4,5-P 3 formation was observed if they were stimulated with IL-8, fMLP, LTB 4 or C5a (Hirsch et al., Science. 2000 Feb. 11; 287(5455):1049-53).
• isolated neutrophils and macrophages from the PI3K ⁇ -deficient mice exhibited a sharply reduced chemotactic activity or production of oxygen radicals compared with a whole series of chemokines and chemoattractors. Also reduced was the IgE-mediated activation of mast cells which had been isolated from p110 ⁇ -deficient mice.
• the mechanism responsible might be a positive feedback mechanism in which the PI3K ⁇ is activated by G i -coupling adenosine A 3 receptors (Laffargue et al., Immunity. 2002 March; 16(3):441-51).
• mice have normal viability and reproductive powers and have the same life expectancy as wild-type comparison animals reared identically. From this it can be concluded that the class IB PI3K ⁇ plays a central role in the activation of various inflammatory cells, and therefore isoform-specific inhibitors represent an attractive possibility for anti-inflammatory therapy with comparatively minor side effects (Ward and Finan, Curr Opin Pharmacol. 2003 August; 3(4):426-34). Apart from its function in leukocytes PI3K ⁇ also appears to be involved in the cardiovascular system, despite its low expression in cardiomyocytes.
• p110 ⁇ -deficient mice exhibited an increase in cardiac muscle contractility which may presumably be explained by an overproduction of cAMP (Crackower et al., Cell. 2002 Sep. 20; 110(6):737-49). It has only recently been possible to demonstrate that PI3K ⁇ is also involved in the development of cardiac hypertrophy. Thus, p110 ⁇ -deficient mice exhibited significantly reduced hypertrophy and fibrosis compared with wild-type animals in an isoproterenol-induced cardiac insufficiency model (Oudit et al., Circulation. 2003 Oct. 28; 108(17):2147-52).
• the problem of the present invention was to provide new compounds which by virtue of their pharmaceutical efficacy as PI3-kinase modulators may be used in the therapeutic field for the treatment of inflammatory or allergic diseases.
• inflammatory and allergic respiratory complaints include inflammatory and allergic respiratory complaints, inflammatory diseases of the gastrointestinal tract, rheumatoid arthritis, inflammatory and allergic skin diseases, inflammatory eye diseases, diseases of the nasal mucosa, inflammatory or allergic conditions involving autoimmune reactions, or inflammation of the kidneys.
• PI3-kinase inhibitors for the treatment of inflammatory diseases are known in the literature.
• WO 03/072557 discloses 5-phenylthiazole derivatives
• WO 04/029055 discloses annelated azolepyrimidines
• WO 04/007491 discloses azolidinone-vinyl linked benzene derivatives.
• the two specifications WO 04/052373 and WO 04/056820 disclose benzoxazine into benzoxazin-3-one derivatives.
• Preferred compounds of formula 1 mentioned above are those wherein
• Preferred compounds of formula 1 mentioned above are those wherein
• Preferred compounds of formula 1 mentioned above are those wherein
• Preferred compounds of formula 1 mentioned above are those wherein
• Preferred compounds of formula 1 mentioned above are those wherein
• Preferred compounds of formula 1 mentioned above are those wherein
• Preferred compounds of formula 1 mentioned above are those wherein
• Preferred compounds of formula 1 mentioned above are those wherein
• Preferred compounds of formula 1 mentioned above are those wherein
• Preferred compounds of formula 1 mentioned above are those wherein
• Particularly preferred of the above-mentioned compounds of formula 1 are the compounds of formula 1.1 wherein R a , R b and R c have the meanings given above, and the pharmacologically acceptable salts, diastereomers, enantiomers, racemates, hydrates or solvates thereof.
• Particularly preferred of the above-mentioned compounds of formula 1 are the compounds of formula 1.2 wherein R a , R b and R c have the meanings given above, and the pharmacologically acceptable salts, diastereomers, enantiomers, racemates, hydrates or solvates thereof.
• Particularly preferred of the above-mentioned compounds of formula 1 are the compounds of formula 1.3 wherein R a , R b and R c have the meanings given above, and the pharmacologically acceptable salts, diastereomers, enantiomers, racemates, hydrates or solvates thereof.
• Particularly preferred of the above-mentioned compounds of formula 1 are the above-mentioned compounds of formula 1.4 wherein R a , R b and R c have the meanings given above, and the pharmacologically acceptable salts, diastereomers, enantiomers, racemates, hydrates or solvates thereof.
• Preferred compounds of formula 1 mentioned above are those wherein
• Preferred compounds of formula 1 mentioned above are those wherein
• Preferred compounds of formula 1 mentioned above are those wherein
• R a denotes propyl, COR 8 , NR 9 R 10 , S(O) n R 11 and R 8 denotes furanyl;
• R 9 denotes methyl;
• R 10 denotes methyl;
• R 11 denotes ethyl;
• n denotes 0;
• R b denotes H or OH;
• R c denotes NH 2 or NHCOCH 3 ; and the pharmacologically acceptable salts, diastereomers, enantiomers, racemates, hydrates or solvates thereof.
• C 1-6 -alkyl (including those which are part of other groups) are meant branched and unbranched alkyl groups with 1 to 6 carbon atoms, and by the term “C 1-4 -alkyl” are meant branched and unbranched alkyl groups with 1 to 4 carbon atoms.
• Alkyl groups with 1 to 4 carbon atoms are preferred. Examples of these include: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl or hexyl.
• Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. may optionally also be used for the above-mentioned groups.
• the definitions propyl, butyl, pentyl and hexyl include all the possible isomeric forms of the groups in question.
• propyl includes n-propyl and iso-propyl
• butyl includes iso-butyl, sec-butyl and tert-butyl etc.
• C 1-6 -alkylene (including those which are part of other groups) are meant branched and unbranched alkylene groups with 1 to 6 carbon atoms and by the term “C 1-4 -alkylene” are meant branched and unbranched alkylene groups with 1 to 4 carbon atoms.
• Alkylene groups with 1 to 4 carbon atoms are preferred. Examples include: methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, pentylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene or hexylene.
• propylene, butylene, pentylene and hexylene also include all the possible isomeric forms of the relevant groups with the same number of carbons.
• propyl also includes 1-methylethylene and butylene includes 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene.
• C 2-6 -alkenyl denotes branched and unbranched alkenyl groups with 2 to 6 carbon atoms and the term “C 2-4 -alkenyl” denotes branched and unbranched alkenyl groups with 2 to 4 carbon atoms, provided that they have at least one double bond.
• alkenyl groups with 2 to 4 carbon atoms examples include: ethenyl or vinyl, propenyl, butenyl, pentenyl, or hexenyl. Unless otherwise stated, the definitions propenyl, butenyl, pentenyl and hexenyl include all possible isomeric forms of the groups in question. Thus, for example, propenyl includes 1-propenyl and 2-propenyl, butenyl includes 1-, 2- and 3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl etc.
• C 2-6 -alkenylene (including those which are part of other groups) are meant branched and unbranched alkenylene groups with 2 to 6 carbon atoms and by the term “C 2-4 -alkenylene” are meant branched and unbranched alkylene groups with 2 to 4 carbon atoms. Alkenylene groups with 2 to 4 carbon atoms are preferred.
• Examples include: ethenylene, propenylene, 1-methylethenylene, butenylene, 1-methylpropenylene, 1,1-dimethylethenylene, 1,2-dimethylethenylene, pentenylene, 1,1-dimethylpropenylene, 2,2-dimethylpropenylene, 1,2-dimethylpropenylene, 1,3-dimethylpropenylene or hexenylene.
• the definitions propenylene, butenylene, pentenylene and hexenylene include all the possible isomeric forms of the respective groups with the same number of carbons.
• propenyl also includes 1-methylethenylene and butenylene includes 1-methylpropenylene, 1,1-dimethylethenylene, 1,2-dimethylethenylene.
• C 2-6 -alkynyl (including those which are part of other groups) are meant branched and unbranched alkynyl groups with 2 to 6 carbon atoms and by the term “C 2-4 -alkynyl” are meant branched and unbranched alkynyl groups with 2 to 4 carbon atoms, provided that they have at least one triple bond.
• Alkynyl groups with 2 to 4 carbon atoms are preferred. Examples include: ethynyl, propynyl, butynyl, pentynyl, or hexynyl.
• propynyl, butynyl, pentynyl and hexynyl include all the possible isomeric forms of the respective groups.
• propynyl includes 1-propynyl and 2-propynyl
• butynyl includes 1-, 2- and 3-butynyl, 1-methyl-1-propynyl, 1-methyl-2-propynyl etc.
• C 2-6 -alkynylene (including those which are part of other groups) are meant branched and unbranched alkynylene groups with 2 to 6 carbon atoms and by the term “C 2-4 -alkynylene” are meant branched and unbranched alkylene groups with 2 to 4 carbon atoms. Alkynylene groups with 2 to 4 carbon atoms are preferred.
• Examples include: ethynylene, propynylene, 1-methylethynylene, butynylene, 1-methylpropynylene, 1,1-dimethylethynylene, 1,2-dimethylethynylene, pentynylene, 1,1-dimethylpropynylene, 2,2-dimethylpropynylene, 1,2-dimethylpropynylene, 1,3-dimethylpropynylene or hexynylene.
• the definitions propynylene, butynylene, pentynylene and hexynylene include all the possible isomeric forms of the respective groups with the same number of carbons.
• propynyl also includes 1-methylethynylene and butynylene includes 1-methylpropynylene, 1,1-dimethylethynylene, 1,2-dimethylethynylene.
• C 1-6 -alkoxy (including those which are part of other groups) are meant branched and unbranched alkoxy groups with 1 to 6 carbon atoms and by the term “C 1-4 -alkoxy” are meant branched and unbranched alkoxy groups with 1 to 4 carbon atoms.
• Alkoxy groups with 1 to 4 carbon atoms are preferred. Examples include: methoxy, ethoxy, propoxy, butoxy or pentoxy.
• the abbreviations OMe, OEt, OPr, etc. may optionally be used for the above-mentioned groups.
• the definitions propoxy, butoxy and pentoxy include all the possible isomeric forms of the respective groups. Thus for example propoxy includes n-propoxy and iso-propoxy, butoxy includes iso-butoxy, sec-butoxy and tert-butoxy etc.
• C 3-8 -cycloalkyl (including those which are part of other groups) are meant cyclic alkyl groups with 3 to 8 carbon atoms
• C 3-6 -cycloalkyl are meant cyclic alkyl groups with 3 to 8 carbon atoms
• C 5-6 -cycloalkyl are meant cyclic alkyl groups with 5 to 6 carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
• C 3-6 -cycloalkenyl (including those which are part of other groups) are meant cyclic alkyl groups with 5 or 6 carbon atoms which contain one or two double bonds. Examples include: cyclopentenyl, cyclopentadienyl, cyclohexenyl or cyclohexadienyl.
• C 1-6 -haloalkyl (including those which are part of other groups) are meant branched and unbranched alkyl groups with 1 to 6 carbon atoms wherein one or more hydrogen atoms are replaced by a halogen atom selected from among fluorine, chlorine or bromine, preferably fluorine and chlorine, particularly preferably fluorine.
• C 1-4 -haloalkyl are meant correspondingly branched and unbranched alkyl groups with 1 to 4 carbon atoms, wherein one or more hydrogen atoms are replaced analogously to what was stated above. C 1-4 -haloalkyl is preferred. Examples include: CH 2 F, CHF 2 , CF 3 ,
• C 7-11 -aralkyl (including those which are part of other groups) are meant branched and unbranched alkyl groups with 1 to 4 carbon atoms which are substituted by an aromatic ring system with 6 carbon atoms. Examples include: benzyl, 1- or 2-phenylethyl. Unless otherwise stated, the aromatic groups may be substituted by one or more groups selected from among methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.
• aryl aromatic ring systems with 6 or 10 carbon atoms. Examples include: phenyl or naphthyl, the preferred aryl group being phenyl.
• heterocyclic rings are meant five-, six- or seven-membered, saturated or unsaturated heterocyclic rings or 5-10 membered, bicyclic hetero rings which may contain one, two or three heteroatoms, selected from among oxygen, sulphur and nitrogen; the ring may be linked to the molecule by a carbon atom or, if present, by a nitrogen atom.
• heterocyclic rings include five-, six- or seven-membered, saturated or unsaturated heterocyclic rings:
• heterocyclic ring may be provided with a keto group.
• examples include:
• 5- 10-membered bicyclic heterorings are pyrrolizine, indole, indolizine, isoindole, indazole, purine, quinoline, isoquinoline, benzimidazole, benzofuran, benzopyran, benzothiazole, benzoisothiazole, pyridopyrimidine, pteridine, pyrimidopyrimidine,
• heterocyclic rings includes (“hetaryl”)
• heterocyclic aromatic groups denotes five- or six-membered heterocyclic aromatic groups or 5-10 membered, bicyclic hetaryl rings which may contain one, two or three heteroatoms, selected from among oxygen, sulphur and nitrogen, which contain sufficient conjugated double bonds that an aromatic system is formed.
• the ring may be linked to the molecule through a carbon atom or if present through a nitrogen atom.
• 5- 10-membered bicyclic hetaryl rings examples include pyrrolizine, indole, indolizine, isoindole, indazole, purine, quinoline, isoquinoline, benzimidazole, benzofuran, benzopyran, benzothiazole, benzoisothiazole, pyridopyrimidine, pteridine, pyrimidopyrimidine.
• heterocyclic spiro rings 5-10 membered, spirocyclic rings which may optionally contain one, two or three heteroatoms, selected from among oxygen, sulphur and nitrogen, while the ring may be connected to the molecule via a carbon atom or, if present, via a nitrogen atom.
• a spirocyclic ring may be provided with a keto group. Examples include:
• lower-molecular groups regarded as chemically meaningful are groups consisting of 1-200 atoms. Preferably such groups have no negative effect on the pharmacological efficacy of the compounds.
• the groups may comprise:
• a suspension of 1.5 g (63 mmol) sodium hydride (60% suspension in mineral oil) in 80 ml DMF is combined batchwise with 8 g (63 mmol) methyl imidazole-4-carboxylate and the resulting solution is stirred for 1 hour.
• the reaction mixture is cooled to 5° C. and 12 ml (70 mmol) [2-(trimethylsilyl)-ethoxy]methyl chloride are added. After 12 hours the suspension is combined with 100 ml of water and extracted with ethyl acetate. The combined organic phases are washed with sodium chloride solution, dried and evaporated down.
• trans-dibenzyl-4-morpholino-cyclohexylamine may be prepared as follows:
• intermediate compound 24.8 g product Z5e are obtained from 7.5 g (40 mmol) intermediate compound 1, 7.7 g (110 mmol) sodium methoxide and 15.1 ml (110 mmol) ethyl furan-3-carboxylate.
• intermediate compound 10 Analogously to the preparation of intermediate compound 101.8 g product Z5k are obtained from 4.2 g (20 mmol) intermediate compound 1, 60 ml (60 mmol) LiHMDS (1 M in hexane) and 5.6 g (40 mmol) 1-imidazol-1-yl-2-methoxy-ethanone.
• Example 14 g product are obtained from 15 g (63 mmol) intermediate compound 2 and 9.8 g (64 mmol) 4-nitrophenylhydrazine (M.p.: 300-310° C.).
• Example 11 0.1 g (0.2 mmol) of the compound obtained in Example 11 are suspended in 0.5 ml trifluoroacetic acid and 2 ml dichloromethane and stirred overnight at ambient temperature. The reaction mixture is evaporated down, the residue taken up in acetone and the product is precipitated by the addition of ethereal hydrochloric acid.
• Example 23 0.2 g (0.85 mmol) of the intermediate described in Example 20/21 are suspended in 2 ml benzene and combined with 0.25 ml (1.80 mmol) triethylamine and 0.18 ml (1.55 mmol) benzoyl chloride. The reaction mixture is stirred for 2 hours at 75° C. Then the suspension is suction filtered, the precipitate is washed with ethyl acetate and water. Yield: 0.12 g (m.p.: 266-267° C., Example 23)
• the mother liquor is concentrated by evaporation and the residue is purified by chromatography.
• Example 2 Analogously to Example 1 a mixture of the two possible pyrazole isomers is obtained from 3.3 g (11 mmol) intermediate compound 4 and 2.1 g (11 mmol) methyl 3-chloro-4-hydrazino-benzoate, and these are separated by column chromatography.
• Example 28 Analogously to Example 1,102 mg (M.p. 265-266° C., Example 27); 12 mg (m.p.: >300° C., Example 28) are obtained from 0.5 g (1.2 mmol) intermediate compound 6 and 0.2 g (1.2 mmol) 2-chloro-phenylhydrazine-hydrochloride after purification by column chromatography.
• Example 2 Analogously to Example 1, 0.22 g product are obtained from 0.2 g (0.7 mmol) intermediate compound 13 and 0.13 g (0.7 mmol) 2-chloro-phenylhydrazine hydrochloride.
• Example 2 Analogously to Example 1, 1.2 g of product, whose ester function is saponified with 0.2 g (8.4 mmol) lithium hydroxide analogously to Example 26, is obtained from 0.9 g (3.2 mmol) intermediate compound 13 and 0.7 g (3.2 mmol) methyl 3-chloro-4-hydrazino-benzoate. Then 50 mg of the acid obtained are subjected to amide coupling with methylaminopiperidine as described in Example 26.
• Example 34 0.5 g product is obtained from 1.5 g of the acid described in Example 33, 1 ml (4.6 mmol) DPPA and 0.6 ml (4.4 mmol) triethylamine in 20 ml dimethylacetamide and subsequent reaction with 2 g p-toluenesulphonic acid and 10 ml of water.
• Example 36 Analogously to Example 36 the desired product is obtained by using methylamine.
• 0.1 g (0.26 mmol) of the compound described in Example 32 are placed in 5 ml dichloromethane and 0.1 g (0.28 mmol) HATU (o-7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate) are added. Then the mixture is combined with 0.09 ml (0.53 mmol) diisopropylethylamine and 0.03 ml (0.28 mmol) morpholine. The reaction mixture is stirred for 4 hours at ambient temperature, then extracted with dichloromethane and water. The organic phase is dried and evaporated to dryness. The residue is purified by chromatography. Corresponding fractions are combined, concentrated by evaporation, dissolved in water and made basic with sodium hydrogen carbonate solution. The precipitated solid is suction filtered and dried. Yield: 0.02 g
• Example 16.4 g product are obtained from 10 g (32 mmol) intermediate compound 8 and 1.7 g (33 mmol) hydrazine-hydrate.
• Example 42 100 mg (M.p.: >300° C., Example 42) and 4 mg (Example 43) are obtained from 0.25 g (0.8 mmol) intermediate compound 11 and 0.14 g (0.8 mmol) 2-chloro-phenylhydrazine-hydrochloride after purification by column chromatography.
• Example 2 Analogously to Example 1, 0.2 g product are obtained from 0.25 g (0.9 mmol) intermediate compound 12 and 0.16 g (0.9 mmol) 2-chloro-phenylhydrazin-hydrochloride after purification by column chromatography.
• Example 2 Analogously to Example 1, 0.68 g product, the ester function of which is saponified with 0.1 g lithium hydroxide analogously to Example 26, is obtained from 3.25 g (10.7 mmol) intermediate compound 12 and 2.14 g (10.7 mmol) methyl 3-chloro-4-hydrazinebenzoate. Then 40 mg of the acid obtained are subjected to amide is coupling with methylaminopiperidine as described in Example 26.
• Example 10 Analogously to Example 10.16 g product are obtained from 0.25 g (1.0 mmol) intermediate compound 10 and 0.18 g (1.0 mmol) 2-chloro-phenylhydrazine-hydrochloride.
• Example 10 Analogously to Example 10.06 g product are obtained from 0.1 g (0.3 mmol) intermediate compound 9 and 0.06 g (0.3 mmol) 2-chloro-phenylhydrazine-hydrochloride after purification by column chromatography.
• Example 1 Analogously to Example 1, 0.5 g intermediate product are obtained from 0.6 g (1.4 mmol) intermediate compound 17 and 0.3 g (1.4 mmol) 2-chlorophenylhydrazine hydrochloride. This is converted into the desired product with 1.7 ml (1.7 mmol) tetrabutylammonium fluoride solution (1 M in THF) as described in Example 50.
• Example 10.23 g product are obtained from 0.25 g (0.8 mmol) intermediate compound 14 and 0.15 g (0.8 mmol) 2-chloro-phenylhydrazine-hydrochloride after purification by column chromatography.
• Example 1116 g product, the ester function of which is saponified with 0.2 g lithium hydroxide analogously to Example 26, is obtained from 1.25 g (4.1 mmol) intermediate compound 14 and 0.82 g (4.1 mmol) methyl 3-chloro-4-hydrazine benzoate. Then 50 mg of the acid obtained are subjected to amide coupling with 4-picolylamine as described in Example 26.
• Example 10 Analogously to Example 10.08 g product are obtained from 0.1 g (0.3 mmol) intermediate compound 15 and 0.05 g (0.3 mmol) 2-chloro-phenylhydrazine-hydrochloride after purification by column chromatography.
• Example 10 Analogously to Example 10.02 g product are obtained from 0.1 g (0.3 mmol) intermediate compound 16 and 0.06 g (0.3 mmol) 2-chlorophenylhydrazine-hydrochloride after purification by column chromatography.
• Example 10.05 g product are obtained from 0.3 g (0.9 mmol) intermediate compound 16 and 0.16 g (0.9 mmol) 2-(trifluoromethyl)phenylhydrazine after purification by column chromatography.
• 0.04 g are placed in 5 ml THF and combined with 0.1 ml (0.1 mmol) tetrabutylammonium fluoride solution (1 M in THF). The mixture is stirred for 0.5 hours at ambient temperature and then water is added. The aqueous phase is extracted with ethyl acetate, the organic phase is washed with water and 1 N hydrochloric acid. The organic phase is dried and evaporated to dryness. The residue is purified by chromatography. Yield: 0.012 g
• Example 10 Analogously to Example 10.04 g product are obtained from 0.3 g (1.0 mmol) intermediate compound 19 and 0.15 g (1.0 mmol) phenylhydrazine-hydrochloride.
• Example 5914 mg product are obtained from 140 mg (0.5 mmol) N-(4-o-tolyl-4,7-dihydro-3-thia-1,4,5-triaza-cyclopenta[a]pentalen-2-yl)-acetamide (prepared analogously to Example 58) in 1 ml of water and 1 ml hydrochloric acid after purification by column chromatography.
• Example 59 Analogously to Example 59, 2.5 g of a compound are obtained from 3.9 g (11.7 mmol) 4-(2-chloro-phenyl)-4,7-dihydro-3-thia-1,4,5-triaza-cyclopenta[a]pentalen-2-ylamine (prepared analogously to Example 58), of which 0.7 g (1.7 mmol) are reacted as in Example 61 to form 0.2 g product (m.p.: 167-170° C.).
• Example 710.14 g product (M.p.: 292-295° C.) may be obtained from 0.20 g (0.7 mmol) N-(8-dimethylamino-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl)-acetamide (obtained analogously to Example 58).
• Example 71 0.3 g (1.1 mmol) of the compound obtained in Example 71 are suspended in 15 ml dichloromethane, combined with 0.4 ml (2.5 mmol) triethylamine and gently refluxed. 0.2 ml (2.3 mmol) propionic acid chloride are added and the mixture is refluxed for 5 hours with stirring. After cooling to ambient temperature the reaction solution is washed with sodium hydrogen carbonate and water, dried and evaporated to dryness. The residue is stirred with diethyl ether and suction filtered.
• Example 73 Analogously to Example 73, 0.03 g product are obtained from 0.15 g (0.5 mmol) of the compound obtained in Example 71, 1 ml triethylamine and 0.2 g (1.3 mmol) 4-dimethylamine-butyric acid chloride-hydrochloride.
• 0.1 g (0.27 mmol) of the previously prepared compound and 0.1 g O-(1H-benzotriazol-1-yl)-N,N, N′,N′-tetramethyluronium-tetrafluoroborate (TBTU) are placed in 2 ml of dimethylformamide, combined with 0.2 ml diisopropylethylamine and stirred for 0.5 hours at ambient temperature.
• 0.2 ml (4.0 mmol) dimethylamine (2 M in THF) are added and the mixture is stirred for a further 16 hours at ambient temperature.
• the resulting suspension is dissolved with dimethylformamide, then purified by RP-HPLC. Corresponding fractions are combined and freeze-dried.
• Example 82 0.05 g (0.13 mmol) of the compound obtained in Example 82 are dissolved in 5 ml ethereal hydrochloric acid and stirred for 16 hours at ambient temperature. The resulting solid is suction filtered, triturated with diethyl ether/acetone 9:1 and suction filtered again. Yield: 0.03 g
• Example 860.075 g product (M.p.: 272-274° C.) may be obtained from 0.1 g (0.4 mmol) of the intermediate described therein, 0.045 g (0.4 mmol) isobutyric acid chloride and 0.1 ml triethylamine in 5 ml dichloromethane.
• an in-vitro kinase assay is set up which is based on the transfer of the terminal ⁇ -phosphate of ATP to phosphatidylinositol-4,5-bisphosphate (PIP 2 ).
• the enzyme activity used is the G ⁇ 1 ⁇ 2 -His stimulated PI3K ⁇ .
• the kinase assay is carried out in white 384-well flat-bottomed dishes. Each well contained 5 ⁇ l of the compound to be tested which had been dissolved in assay buffer (40 mM Hepes, pH 7.5, 100 mM NaCl, 1 mM EGTA, 1 mM ⁇ -glycerophosphate, 1 mM DTT, 7 mM MgCl 2 and 0.1% BSA; 6% DMSO). 15 ⁇ l of lipid vesicles containing 10 ng of PI3K ⁇ and 31.5 ng of G ⁇ 1 ⁇ 2 -His were added in each case.
• assay buffer 40 mM Hepes, pH 7.5, 100 mM NaCl, 1 mM EGTA, 1 mM ⁇ -glycerophosphate, 1 mM DTT, 7 mM MgCl 2 and 0.1% BSA; 6% DMSO.
• the lipid vesicles in turn were generated by suspending PIP 2 (0.35 ⁇ g/well), phosphatidyl ethanolamine (3.75 ⁇ g/well), phosphatidyl serine (3.5 ⁇ g/well), sphingomyelin (0.35 ⁇ g/well) and phosphatidyl choline (1.6 ⁇ g/well) in lipid buffer (assay buffer without DMSO) by ultrasound treatment.
• reaction After the addition of the lipid vesicles the reaction is started by the addition of 10 ⁇ l reaction buffer (40 mM Hepes, pH 7.5, 100 mM NaCl, 1 mM EGTA, 1 mM ⁇ -glycerophosphate, 1 mM DTT, 7 mM MgCl 2 and 0.1% BSA; 1 ⁇ M ATP and 0.2 ⁇ Ci [ ⁇ - 33 P]-ATP).
• 10 ⁇ l reaction buffer 40 mM Hepes, pH 7.5, 100 mM NaCl, 1 mM EGTA, 1 mM ⁇ -glycerophosphate, 1 mM DTT, 7 mM MgCl 2 and 0.1% BSA; 1 ⁇ M ATP and 0.2 ⁇ Ci [ ⁇ - 33 P]-ATP).
• the reaction mixture is incubated in this way for 1 h and then stopped by the addition of a suspension of 0.12 mg LEADseeker beads (Amersham Biosciences) in stop buffer (40 mM Hepes, pH 7.5, 100 mM NaCl, 1 mM EGTA, 12 mM EDTA, 1 mM ⁇ -glycerophosphate, 1 mM DTT). After 1 minute's centrifugation at 500 ⁇ g the plates were read and analysed using a LEADseeker apparatus. All the compounds shown have an IC 50 value of less than 800 nM in the test.
• H >300 345. H 298-305 346. H 255-260 347. H 245-252 348. H 288-295 349. H 350. H >300 351. H 296-300 352. H 292-300 353. H >280 354. H 238-243 355. H >300 356. H 205-210 357. H 200-204 358. H 108-115 359. H >300 360. H 175-180 361. H 172-175 362. H 220-222 363. H >250 364. H 239-242 365. H 216-219 366. H >300 367. H 199-201 368. H >300 369. H 246-247
• the compounds of formula 1 are characterised by a variety of possible applications in the therapeutic field. Particular mention should be made of those applications for which the compounds of formula 1 according to the invention are preferably used by virtue of their pharmaceutical activity as PI3-kinasemodulators.
• inflammatory and allergic respiratory complaints inflammatory diseases of the gastrointestinal tract, inflammatory diseases of the motor apparatus, inflammatory and allergic skin diseases, inflammatory eye diseases, diseases of the nasal mucosa, inflammatory or allergic ailments which involve autoimmune reactions or inflammation of the kidneys.
• the treatment may be symptomatic, adaptive, curative or preventative.
• the compounds of formula 1 according to the invention may, by virtue of their pharmacological properties, bring about a reduction in
• the compounds according to the invention are particularly preferred for preparing a medicament for the treatment of chronic bronchitis, acute bronchitis, bronchitis caused by bacterial or viral infection or fungi or helminths, allergic bronchitis, toxic bronchitis, chronic obstructive bronchitis (COPD), asthma (intrinsic or allergic), paediatric asthma, bronchiectasis, allergic alveolitis, allergic or non-allergic rhinitis, chronic sinusitis, cystic fibrosis or mucoviscidosis, alpha-1-antitrypsin deficiency, cough, pulmonary emphysema, interstitial lung diseases such as e.g.
• pulmonary fibrosis pulmonary fibrosis, asbestosis and silicosis and alveolitis
• hyperreactive airways nasal polyps, pulmonary oedema such as e.g. toxic pulmonary oedema and ARDS/IRDS, pneumonitis of different origins, e.g. radiation-induced or by caused by aspiration or infectious pneumonitis, collagenoses such as lupus eryth, systemic sclerodermy, sarcoidosis or Boeck's disease.
• the compounds of formula 1 are also suitable for the treatment of diseases of the skin, such as e.g. psoriasis, contact dermatitis, atopic dermatitis, alopecia greata (circular hair loss), erythema exsudativum multiforme (Stevens-Johnson Syndrome), dermatitis herpetiformis, sclerodermy, vitiligo, nettle rash (urticaria), lupus erythematodes, follicular and surface pyodermy, endogenous and exogenous acne, acne rosacea and other inflammatory or allergic or proliferative skin diseases.
• diseases of the skin such as e.g. psoriasis, contact dermatitis, atopic dermatitis, alopecia greata (circular hair loss), erythema exsudativum multiforme (Stevens-Johnson Syndrome), dermatitis herpetiformis, sclerodermy, vit
• the compounds of formula 1 are suitable for therapeutic use in cases of inflammatory or allergic complaints which involve autoimmune reactions, such as e.g. inflammatory bowel diseases, e.g. Crohn's disease or ulcerative colitis; diseases of the arthritis type, such as e.g. rheumatoid or psoriatic arthritis, osteoarthritis, rheumatoid spondylitis and other arthritic conditions or multiple sclerosis.
• autoimmune reactions such as e.g. inflammatory bowel diseases, e.g. Crohn's disease or ulcerative colitis
• diseases of the arthritis type such as e.g. rheumatoid or psoriatic arthritis, osteoarthritis, rheumatoid spondylitis and other arthritic conditions or multiple sclerosis.
• Other diseases which may be treated with a drug containing compounds of formula 1 on the basis of their pharmacological activity include toxic or septic shock syndrome, atherosclerosis, middle ear infections (otitis media), hypertrophy of the heart, cardiac insufficiency, stroke, ischaemic reperfusion injury or neurodegenerative diseases such as Parkinson's disease or Alzheimer's.
• the compounds of formula 1 may be used on their own or in conjunction with other active substances of formula 1 according to the invention. If desired the compounds of general formula 1 may also be used in conjunction with other pharmacologically active substances.
• active substances are used which are selected, for example, from among the betamimetics, anticholinergics, corticosteroids, PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, dopamine-agonists, H1-antihistamines, PAF-antagonists and PI3-kinase inhibitors or double or triple combinations thereof, such as for example combinations of
• Suitable betamimetics used are preferably compounds selected from among albuterol, arformoterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, isoetharine, isoprenaline, levosalbutamol, mabuterol, meluadrine, metaproterenol, orciprenaline, pirbuterol, procaterol, reproterol, rimiterol, ritodrine, salmefamol, salmeterol, sulphsoterenol, sulphonterol, terbutaline, tiaramide, tolubuterol, zinterol, CHF-1035, HOKU-81, KUL-1248 and
• the anticholinergics used are preferably compounds selected from among the tiotropium salts, preferably the bromide salt, oxitropium salts, preferably the bromide salt, flutropium salts, preferably the bromide salt, ipratropium salts, preferably the bromide salt, glycopyrronium salts, preferably the bromide salt, trospium salts, preferably the chloride salt, tolterodine.
• the cations are the pharmacologically active ingredients.
• the above-mentioned salts may preferably contain chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulphonate, while chloride, bromide, iodide, sulphate, methanesulphonate or p-toluenesulphonate are preferred as counter-ions.
• chloride, bromide, iodide and methanesulphonate are particularly preferred.
• Other named compounds are:
• Corticosteroids used here are preferably compounds selected from among prednisolone, prednisone, butixocortpropionate, flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, dexamethasone, betamethasone, deflazacort, RPR-106541, NS-126, ST-26 and
• PDE4 inhibitors which may be used are preferably compounds selected from among enprofyllin, theophyllin, roflumilast, ariflo (cilomilast), tofimilast, pumafentrin, lirimilast, arofyllin, atizoram, D4418, Bay-198004, BY343, CP-325,366, D-4396 (Sch-351591), AWD-12-281 (GW-842470), NCS-613, CDP-840, D-4418, PD-168787, T440, T-2585, V-11294A, Cl-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370 and
• LTD4-antagonists which may be used are preferably compounds selected from among montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707, L-733321 and
• EGFR-inhibitors which may be used are preferably compounds selected from among cetuximab, trastuzumab, ABX-EGF, Mab ICR-62 and
• Dopamine agonists which may be used are preferably compounds selected from among bromocriptin, cabergolin, alpha-dihydroergocryptin, lisuride, pergolide, pramipexol, roxindol, ropinirol, talipexol, terguride and viozan, optionally in the form of the racemates, enantiomers, diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof.
• the acid addition salts of the Dopamine agonists are selected from among the hydrochloride, hydrobromide, hydroiodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.
• H1-Antihistamines which may be used are preferably compounds selected from among epinastin, cetirizin, azelastin, fexofenadin, levocabastin, loratadin, mizolastin, ketotifen, emedastin, dimetinden, clemastin, bamipin, cexchlorpheniramine, pheniramine, doxylamine, chlorphenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastin, desloratidine and meclozine, optionally in the form of the racemates, enantiomers, diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof.
• the acid addition salts of the H1-Antihistamines are selected from among the hydrochloride, hydrobromide, hydroiodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.
• PAF-Antagonists which may be used are preferably compounds selected from among
• the compounds according to the invention may be administered by oral, transdermal, inhalative, parenteral or sublingual route.
• the compounds according to the invention are present as active ingredients in conventional preparations, for example in compositions consisting essentially of an inert pharmaceutical carrier and an effective dose of the active substance, such as for example tablets, coated tablets, capsules, lozenges, powders, solutions, suspensions, emulsions, syrups, suppositories, transdermal systems etc.
• An effective dose of the compounds according to the invention is between 0.1 and 5000, preferably between 1 and 500, more preferably between 5-300 mg/dose for oral administration, and between 0.001 and 50, preferably between 0.1 and 10 mg/dose for intravenous subcutaneous or intramuscular administration.
• solutions containing 0.01 to 1.0, preferably 0.1 to 0.5% active substance are suitable.
• solutions containing 0.01 to 1.0, preferably 0.1 to 0.5% active substance are suitable.
• the use of powders, ethanolic or aqueous solutions is preferred.
• the compounds according to the invention as a solution for infusion, preferably in a physiological saline or nutrient saline solution.
• the compounds according to the invention may be used on their own or in conjunction with other active substances according to the invention, optionally also in conjunction with other pharmacologically active substances.
• Suitable formulations include, for example, tablets, capsules, suppositories, solutions, syrups, emulsions or dispersible powders.
• Corresponding tablets may be obtained for example by mixing the active substance(s) with known excipients, for example inert diluents, such as calcium carbonate, calcium phosphate or lactose, disintegrants such as maize starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
• excipients for example inert diluents, such as calcium carbonate, calcium phosphate or lactose, disintegrants such as maize starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
• excipients for example inert
• Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
• the core may also consist of a number of layers.
• the tablet coating may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.
• Syrups containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
• a sweetener such as saccharine, cyclamate, glycerol or sugar
• a flavour enhancer e.g. a flavouring such as vanillin or orange extract.
• suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
• Solutions for injection are prepared in the usual way, e.g. with the addition of preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, and transferred into injection vials or ampoules.
• preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid
• Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules.
• Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof.
• a therapeutically effective daily dose is between 1 and 2000 mg, preferably 10-500 mg per adult.
• the active substance, corn starch, lactose and polyvinylpyrrolidone are thoroughly mixed and moistened with water.
• the moist mass is pushed through a screen with a 1 mm mesh size, dried at about 45° C. and the granules are then passed through the same screen.
• convex tablet cores with a diameter of 6 mm are compressed in a tablet-making machine.
• the tablet cores thus produced are coated in a known manner with a covering consisting essentially of sugar and talc.
• the finished coated tablets are polished with wax D)
• the active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic.
• the solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilised and sealed by fusion.
• the ampoules contain 5 mg, 25 mg and 50 mg of active substance.
• Distilled water is heated to 70° C. Hydroxyethyl-cellulose is dissolved therein with stirring. After the addition of sorbitol solution and glycerol the mixture is cooled to ambient temperature. At ambient temperature, sorbic acid, flavouring and substance are added. To eliminate air from the suspension it is evacuated with stirring.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Pulmonology (AREA)
• Dermatology (AREA)
• Rheumatology (AREA)
• Communicable Diseases (AREA)
• Immunology (AREA)
• Oncology (AREA)
• Pain & Pain Management (AREA)
• Ophthalmology & Optometry (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Physical Education & Sports Medicine (AREA)
• Gastroenterology & Hepatology (AREA)
• Virology (AREA)
• Urology & Nephrology (AREA)
• Epidemiology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Priority Applications (1)

Applications Claiming Priority (4)

Related Child Applications (1)

Publications (1)

Family

ID=35583390

Family Applications (4)

Family Applications Before (1)

Family Applications After (2)

Country Status (14)

Cited By (21)

Families Citing this family (22)

Citations (4)

Family Cites Families (22)

• 2005
  • 2005-10-05 US US11/243,796 patent/US7691888B2/en active Active
  • 2005-10-05 CN CNA2005800344060A patent/CN101048418A/zh active Pending
  • 2005-10-05 RU RU2007116861/04A patent/RU2007116861A/ru not_active Application Discontinuation
  • 2005-10-05 BR BRPI0516557-1A patent/BRPI0516557A/pt not_active IP Right Cessation
  • 2005-10-05 KR KR1020077010387A patent/KR20070064660A/ko not_active Application Discontinuation
  • 2005-10-05 US US11/244,299 patent/US20060106013A1/en not_active Abandoned
  • 2005-10-05 WO PCT/EP2005/055015 patent/WO2006040279A1/de active Application Filing
  • 2005-10-05 MX MX2007004051A patent/MX2007004051A/es not_active Application Discontinuation
  • 2005-10-05 AU AU2005293607A patent/AU2005293607A1/en not_active Abandoned
  • 2005-10-05 EP EP11158787A patent/EP2343303A1/de not_active Withdrawn
  • 2005-10-05 JP JP2007535159A patent/JP5122287B2/ja active Active
  • 2005-10-05 EP EP05805652A patent/EP1802636B1/de active Active
  • 2005-10-05 RU RU2007116858/04A patent/RU2403258C2/ru not_active IP Right Cessation
  • 2005-10-05 CA CA2579279A patent/CA2579279C/en active Active
  • 2005-10-06 TW TW094134899A patent/TW200628475A/zh unknown
  • 2005-10-07 AR ARP050104225A patent/AR055273A1/es unknown
• 2007
  • 2007-04-10 IL IL182398A patent/IL182398A0/en unknown
• 2009
  • 2009-02-05 US US12/366,248 patent/US8232286B2/en active Active
• 2010
  • 2010-01-11 US US12/685,213 patent/US8207349B2/en active Active

Patent Citations (4)

Also Published As

Similar Documents

Legal Events